2 AND 3-Substituted-4-(heterocyclic-amino-sulfonyl)benzene sulfonamides

ABSTRACT

Compounds of the formulae: ##SPC1## 
     And the salts thereof with pharmaceutically acceptable cations wherein R 1  is 3-trifluoromethyl, chloro, bromo or fluoro; n and m are each two or three; X is oxygen or sulphur; R 2  and R 3 , when taken separately, are each hydrogen or alkyl having 1 to 4 carbon atoms; R 2  and R 3 , when taken together, are alkylene having 2 to 4 carbon atoms; Y is methylene or a single bond; R 4  and R 5 , when taken separately, are each hydrogen, hydroxy or alkoxy having 1 to 4 carbon atoms, and R 4  and R 5 , when taken together, are oxo or alkylene dioxy having 2 to 4 carbon atoms, each oxygen atom in R 4  and R 5 , when taken separately, and in R 4  and R 5 , when taken together, being separated from the nitrogen atom of the heterocyclic ring by two or more carbon atoms, said compounds being cerebral vasodilators.

This application is a division of application Ser. No. 386,854, filedAug. 9, 1973, and now U.S. Pat. No. 3,867,390 of Feb. 18, 1975.

This invention relates to cyclic N-substituted derivatives of1,4-benzene disulphonamide which have cerebral vasodilator activity andare therefore useful for treating conditions attributable to arestriction of blood flow to the brain. Such conditions includeatherosclerosis, occlusion of blood vessels in the brain, stroke andother cerebrovascular diseases. Particularly useful compounds accordingto this aspect of the invention are those which have a selective effecton the cerebral vasculature, with a comparatively small effect on bloodvessels in other tissues such as peripheral tissue and the kidneys, andso do not cause a serious fall in blood pressure or increase indiuresis.

The aforesaid derivatives include compounds of the formula ##SPC2##

Those of the formula ##SPC3##

And the salts thereof with pharmaceutically acceptable cations whereinR¹ is 3-trifluoromethyl, chloro, bromo or fluoro; n and m are each twoor three; X is oxygen or sulphur; R² and R³, when taken separately, areeach hydrogen or alkyl having 1 to 4 carbon atoms; R² and R³, when takentogether, are alkylene having 2 to 4 carbon atoms; Y is methylene or asingle bond; R⁴ and R⁵, when taken separately, are each hydrogen,hydroxy or alkoxy having 1 to 4 carbon atoms and R⁴ and R⁵, when takentogether, are oxo or alkylene dioxy having 2 to 4 carbon atoms, eachoxygen atom in R⁴ and R⁵, when taken separately, and in R⁴ and R⁵, whentaken together, being separated from the nitrogen atom of theheterocyclic ring by two or more carbon atoms.

Certain of the aforesaid compounds are old in the art as shown in U.S.Pat. No. 3,165,550. Those of the aforesaid compounds of the presentinvention which are unobvious include compounds of formula (I) andformula (II) and the salts thereof with pharmaceutically acceptablecations wherein R¹ is 3-trifluoromethyl, chloro, bromo or fluoro; n andm are each 2 or 3; X is oxygen; R² and R³, when taken separately, areeach alkyl having 1 to 4 carbon atoms; R² and R³, when taken together,are alkylene having 2 to 4 carbon atoms; Y is methylene; R⁴, when takenseparately, is hydroxy or alkoxy having 1 to 4 carbon atoms; R⁵, whentaken separately, is hydrogen, hydroxy or alkoxy having 1 to 4 carbonatoms and R⁴ and R⁵, when taken together, are oxo or alkylene dioxyhaving 2 to 4 carbon atoms, each oxygen atom in R⁴ and R⁵ , when takenseparately, and in R⁴ and R⁵, when taken together, being separated fromthe nitrogen atom of the heterocyclic ring by two or more carbon atoms.

Preferred compounds of the invention having cerebral vasodilatoractivity are those of formula (I) in which X is an oxygen atom. Anotherpreferred group are those compounds of formula (II) in which Y is amethylene group and R⁴ and R⁵ together represent an oxo group or analkylene dioxy group having 1 to 4 carbon atoms, each of these beingattached to the methylene group, i.e., to Y. Another preferred group ofcompounds are those of formula (II) wherein Y is methylene, R⁴ ishydroxy or alkoxy having 1 to 4 carbon atoms and R⁵ is hydrogen. Ofthose preferred compounds of formula (I) in which X is an oxygen atom,particularly preferred are those in which R² and R³ are each alkylhaving 1 to 4 carbon atoms. Of those preferred compounds in which Y is amethylene group or an oxygen atom, particularly preferred are those inwhich n and m are each 2, i.e., the heterocyclic ring is a 4-piperidonering or a dialkyl or alkylene ketal thereof, or a morpholine ring.

Also particularly preferred for their cerebral vasodilator activity arecompounds of the invention having one or more of the preferredstructural characteristics just mentioned wherein R¹ is 2-chloro,2-bromo or 3-trifluoromethyl.

The compounds of this invention, other than those in which R⁴ and R⁵together are an oxo group, may be prepared from 4-sulphamoyl-benzenesulphonyl chlorides of the formula: ##SPC4##

by reaction with a cyclic amine of the formula: ##SPC5##

or with a cyclic amine of the formula: ##SPC6##

in a suitable solvent, e.g., acetone or dichloromethane. Preferably, thereaction is carried out in the presence of an excess of the aminereactant or in the presence of an equivalent amount of an organictertiary amine to remove the hydrochloric acid formed in the reaction.The reaction is completed in from 1 to 24 hours at 20°C. or may becarried out at elevated temperatures, i.e., 30° to 100°C. for periods offrom 1 to 8 hours. The product may be isolated by simply adding thereaction mixture to normal aqueous hydrochloric acid solution,filtering, washing and recrystallizing from a suitable solvent.

Compounds of the invention in which R¹ consists of chloro, bromo, fluoroor trifluoromethyl, in positions meta to the unsubstituted sulphamoylgroup, may also be prepared from the appropriately substituted4-nitrobenzene sulphonyl chloride by reaction first with the cyclicamine of formula (IV) or (V) to form a compound of the formula: ##SPC7##

or of the formula: ##SPC8##

wherein R¹ is a chlorine, bromine or fluorine atom or a trifluoromethylgroup and R⁴ and R⁵, together, are not an oxo group, and the compound offormula (VIII) or (IX) is then reduced to the corresponding aminocompound and the latter is converted to the corresponding sulphamoylcompound by diazotization, treatment with sulphur dioxide in thepresence of a cupric salt and then with ammonia.

Finally compounds in which R⁴ and R⁵ together are an oxo group areprepared from the corresponding dialkyl or alkylene ketals, i.e.,compounds of formula (II) in which R⁴ and R⁵ are two alkoxy groups or analkylene dioxy group attached to a single carbon atom, by methods wellknown in the art, e.g., by treatment with concentrated hydrochloric acidin aqueous dimethylformamide.

The salts of the present invention include those based on anypharmaceutically acceptable cation. The preferred pharmaceuticallyacceptable cations are those of the alkali metals, particularly sodiumand potassium. Said salts are easily obtained in accordance withconventional methods. For example, the selected compound of formula (I)or formula (II) is dissolved in an aqueous or alcoholic solution of analkali metal hydroxide such as sodium or potassium hydroxide and theresulting solution is simply concentrated.

In accordance with the treatment method of the present invention, theherein described compounds can be administered to an affected subjectvia the oral or parenteral route. Generally, there is a significanteffect in increasing cerebral blood flow in cats, dogs and baboons atdose levels of from 2.5 to 25 mg/kg intravenously or from 10 to 50 mg/kgorally when administered three times a day, the effect being cumulative.Although the physician will determine the precise dosage for a humanpatient, it generally will range from 0.5 to 100 mg/kg for intravenousadministration and from 2 to 200 mg/kg for oral administration, eachdosage form being administered four times a day.

The compounds of the invention may be administered alone, but willgenerally be administered in admixture with a pharmaceutical carrierselected with regard to the intended route of administration andstandard pharmaceutical practice.

For administration orally in the form of tablets or capsules, it hasbeen found advantageous to dissolve or disperse the compound in finelydivided form (e.g. 30 microns or less in dimensions) in a matrix of ahigh molecular weight solid polyethylene glycol, e.g. a polyethyleneglycol of average molecular weight 6,000 to 7,500 such as "Carbowax"6,000. A non-ionic wetting agent as dispersion aid, e.g. apolyoxyethylene mono-stearate of average molecular weight about 1,000such as "Myrj" 52, is preferably also included. For this type offormulation, the compound together with the dispersion aid may bedissolved in the molten polyethylene glycol and cooled, or alternativelymay be mixed as an aqueous dispersion with the polyethylene glycol toform a paste and dried, and then, together with other excipients ifdesired, either granulated prior to compression into tablets or filleddirectly into capsules, by techniques well known in the art.

Alternatively, tablets may be formed in which a major part of theexcipient is composed of a material which, when compressed, has a slowerrate of dissolution than that normally achieved by standard tabletingpractice. Such materials include sugars and edible aminoacids such asglycine. The compound (in finely divided form) is preferably first mixedwith the said material and then granulated with a comparatively smallamount of the high molecular weight polyethylene glycol and a dispersionaid, before forming into tablets in the usual way.

For parenteral administration, the compounds, being acidic, are bestused in the form of sterile aqueous solutions of their alkali metal(e.g. sodium) salts and such solutions may contain other solutes (e.g.sodium chloride) to ensure the stability of the solutions and theircompatibility with body fluids, e.g. blood, when the compound is to beadministered intravenously, intra-muscularly or subcutaneously. Thealkali metal salt solution may conveniently be formed by dissolving thecompound (and any other solute required) in the sterile water andadjusting the pH to a value in the range from 10.5 to 12.0 with theappropriate alkali metal hydroxide.

The following examples illustrate preparation of the cerebralvasodilators of this invention.

EXAMPLE I 2-Chloro-4-(4-methoxypiperidinosulphonyl)benzene sulphonamide

Triethylamine (4.2 ml) and 4-methoxypiperidine (3.15 g) were added to asolution of 3-chloro-4-sulphamoyl-benzene sulphonyl chloride (8.7 g) inacetone (100 ml). The mixture was stirred at room temperature for 1 hourand then poured into 50 ml of N-hydrochloric acid. The resulting productwas removed by filtration, washed with water and recrystallized fromisopropanol to give the desired compound (8.4 g), m.p. 165°-167°C.

Analysis: Found: C, 39.16; H, 4.91; N, 7.53%; Calculated for C₁₂ H₁₇ClN₂ O₅ S₂ : C, 39.06; H, 4.64; N, 7.59%.

EXAMPLES II to XXII

The compounds shown in Table I were prepared by the method of Example I,using the appropriate cyclic amine and substituted 4-sulphamoyl-benzenesulphonyl chloride as starting material. The R¹ -substituted4-sulphamoyl-benzene sulphonyl chloride starting materials for theseExamples, as well as for Example I, are either known compounds,disclosed in U.S. Pat. No. 3,165,550, or are readily prepared by themethods described therein, from the corresponding R¹ -substituted4-aminobenzene sulphonamides.

The compounds of Table I are represented by the formula: ##SPC9##

                                      TABLE I                                     __________________________________________________________________________                                 Analysis %                                                                    (theoretical in brackets)                        Example                                                                            R.sup.1                                                                           N-heterocycle m.p.° C.                                                                     C    H   N                                       __________________________________________________________________________    II   3-Cl                                                                               ##STR1##     122-123                                                                             39.08 (39.06                                                                       4.81 4.64                                                                         7.96 7.59)                              III  2-Cl                                                                               ##STR2##     230-234                                                                             37.50 (37.23                                                                       4.26 4.26                                                                         8.12 7.90)                              IV   2-Cl                                                                               ##STR3##     175-177                                                                             40.93 (40.84                                                                       5.09 4.86                                                                         7.84 7.94)                              V    2-Cl                                                                               ##STR4##     187-188                                                                             35.48 (35.25                                                                       3.84 3.82                                                                         8.58 8.22)                              VI   2-Cl                                                                               ##STR5##     151-152                                                                             39.19 (39.06                                                                       4.76 4.64                                                                         7.84 7.59)                              VIII 2-Cl                                                                               ##STR6##     198-199                                                                             38.95 (39.09                                                                       4.62 4.64                                                                         7.96 7.59)                              IX   3-Cl                                                                               ##STR7##     95-98 34.97 (35.25                                                                       4.15 3.82                                                                         8.38 8.22)                              X    2-F                                                                                ##STR8##     199-200                                                                             41.00 (40.90                                                                       4.87 4.86                                                                         7.80 7.95)                              XI   2-Cl                                                                               ##STR9##     172   39.52 (39.34                                                                       4.31 4.31                                                                         7.15 7.06)                              XIII 2-Cl                                                                               ##STR10##    130-132                                                                             37.42 (37.23                                                                       4.43 4.26                                                                         8.33 7.90)                              XIV  2-F                                                                                ##STR11##    176-178                                                                             41.02 (40.89                                                                       4.93 4.86                                                                         7.95 7.95)                              XV   2-Cl                                                                               ##STR12##    193-195                                                                             39.4 (40.0                                                                         4.3 4.45                                                                          8.8 8.3)                                XVI  2-Br                                                                               ##STR13##    161-163                                                                             34.86 (34.93                                                                       4.14 4.15                                                                         6.71 6.79)                              XVII 2-Cl                                                                               ##STR14##    179-180                                                                             33.74 (33.67                                                                       3.73 3.64                                                                         7.54 7.85)                              XVIII                                                                              2-Cl                                                                               ##STR15##    159-162                                                                             37.58 (37.23                                                                       4.31 4.26                                                                         7.82 7.89)                              XIX  2-Cl                                                                               ##STR16##    169-173                                                                             39.37 (39.07                                                                       4.69 4.65                                                                         7.40 7.59)                              XX   2-Cl                                                                               ##STR17##    123-125                                                                             42.78 (42.36                                                                       5.51 5.33                                                                         6.85 7.06)                              XXI  2-Cl                                                                               ##STR18##    176-178                                                                             39.09 (39.29                                                                       4.14 4.09                                                                         7.71 7.64)                              XXII 2-Br                                                                               ##STR19##    200-202                                                                             34.91 (34.94                                                                       4.10 4.15                                                                         7.07 6.79)                              XII  2-Cl                                                                               ##STR20##    198-200                                                                             43.01 (42.58                                                                       5.24 4.85                                                                         7.34 7.10)                              VII  2-Br                                                                               ##STR21##    215-216                                                                              38.35 (38.26                                                                      4.36 4.36                                                                         6.32 6.38)                              __________________________________________________________________________

EXAMPLE XXIII 2-Chloro-4-(4-oxopiperidinosulphonyl)-benzene sulphonamide

A solution of the product of Example XI (1.2 g) in 30% aqueousdimethylformamide (50 ml) and concentrated hydrochloric acid (1.5 ml)was stirred under reflux for 1 hour. The mixture was evaporated to smallvolume and the resulting precipitate was filtered off and recrystallizedfrom an acetone-hexane mixture to give the desired product (500 mg),m.p. 195°-196°C.

Analysis: Found: C, 37.33; H, 3.82; N, 7.96%; Calculated for C₁₁ H₁₃ClN₂ O₅ S₂ : C, 37.50; H, 3.69; N, 7.62%.

EXAMPLE XXIV 3-Trifluoromethyl-4-(4-methoxypiperidinosulphonyl)-benzenesulphonamide

A. Triethylamine (1.0 g) and 4-methoxypiperidine (1.15 g) were added toa solution of 4-nitro-2-trifluoromethylbenzene sulphonyl chloride (2.89g) in methylene chloride (40 ml). The mixture was stirred at 25°C. for 2hours and then evaporated to dryness in vacuo. The residual oil wastriturated with 1:1 aqueous isopropanol and the resulting solid wasrecrystallized from isopropanol to give1-(4-methoxypiperidinosulphonyl)-4-nitro-2-trifluoromethyl-benzene, m.p.141°-143°C.

B. The product of (A) (13.5 g) was dissolved in methanol (200 ml) andhydrogenated at 50 p.s.i. and 50°C. in the presence of 5%palladium-on-charcoal (1.0 g) to yield4-(4-methoxypiperidinosulphonyl)-3-trifluoromethyl-aniline (8.9 g), m.p.145°-147°C., recrystallized from isopropanol.

C. A solution of the diazonium chloride of the product of (B), preparedby the addition of a solution of sodium nitrite (1.73 g) in water (15ml) to the product of (B) (8.4 g) in concentrated hydrochloric acid (60ml), was added at 25°C. to a suspension of cupric chloride dihydrate(2.2 g) in acetic acid (80 ml) previously saturated with sulphurdioxide. The mixture was stirred for 1 hour and the resultingprecipitate was filtered, washed with water, dried and recrystallizedfrom an acetone-hexane mixture to give4-(4-methoxypiperidinosulphonyl)-3-trifluoromethyl-benzene sulphonylchloride (5 g), m.p. 117°-119°C.

D. The product of (C) (4.5 g) was added to concentrated ammoniumhydroxide (80 ml) and the mixture was heated at 60°C for 1 hour. Theresulting solution was cooled, treated with excess 2N hydrochloric acidand the precipitate thus obtained was filtered, washed with water, driedand recrystallized from isopropanol to give the required product (2.3g), m.p. 136°-137°C.

Analysis: Found: C, 38.74; H, 4.22; N, 6.62%; Calculated for C₁₃ H₁₇ F₃N₂ O₅ S₂ : C, 38.81; H, 4.26; N, 6.97%.

The activity of compounds of the invention as cerebral vasodilators isdetermined by the following method. Cats are anaesthetised withchloralose (80 mg/kg, intravenously) after induction with halothane,nitrous oxide/oxygen (3:1 v/v). The animals are allowed to breathenormal room air and the rate and depth of respiration, heart rate andfemoral arterial pressure are recorded. Electromagnetic flow probes areplaced around the ipsilateral vertebral artery. Zero flow is establishedby momentarily occluding the arteries in order to calibrate the flowprobes. The test compound (dissolved in N/10 sodium hydroxide inisotonic saline with warming and mixing and then back titration to pH 10with dilute hydrochloric acid) is given at 10 or 25 mg/kg via a femoralvein and readings are taken at intervals for up to 2 hours. Controlobservations after administration of the saline vehicle alone are alsomade. The criterion for selecting the preferred compounds is on thebasis of increases in ipsilateral vertebral arterial flow at 10 mg/kgwhich are sustained over a period of 30 minutes as shown in Table II.Blood flow is assessed by measuring the peak (systolic) pulsatile flowand the mean pulsatile flow. The products of Examples VIII, XXII, IIIand V have been found to give significant increases in peak and meanpulsatile flow at 10 mg/kg. The product of Example VIII is outstandingat that dosage. Table II hereinafter summarizes results obtained withrepresentative cerebral vasodilators of the present invention inaccordance with this method.

The effect of compounds of the invention on blood pressure and diuresisis determined in dogs by standard methods. Several compounds have beenfound to be particularly advantageous in having very little hypotensiveor diuretic activity, including the products of Examples I and XXII.

                                      TABLE II                                    __________________________________________________________________________                Activity Data.sup.(1)                                             Compound of                                                                          Dose                                                                   Example                                                                              (mg/kg)                                                                            IVF:%                                                                              t     Side Effects                                           __________________________________________________________________________    I      10   42   40-50 --                                                     II     10   10    5-10 --                                                            25   (200)                                                                              20-30 fasciculation at 20 min.                               V      10   40   30-60 --                                                     VIII   10   82    60-120                                                                             --                                                     X      25   40   40-60 --                                                     XI     10   13   5-8   --                                                     XXII   10   30   40-50 --                                                            25   33   20-30 --                                                     XXIV   10   20    5-10 --                                                            25   70   20-40 --                                                     III    10   34   40-60 --                                                     __________________________________________________________________________     .sup.(1) mean maximum increase in blood flow (%) and duration of action i     minutes (t). IVF = ipsilateral vertebral artial flow.                    

EXAMPLE XXV Tablet formulation

                         mg/tablet                                                Active ingredient.sup.(1)                                                                          100.0                                                    glycine              320.7                                                    PEG 6000.sup.(2)     40.0                                                     Myrj 52.sup.(3)      20.0                                                     magnesium stearate   4.9                                                      gelatin              2.4                                                                           488.0                                                     .sup.(1) mean particle diameter (from surface area/g) less than 16            microns.                                                                      .sup.(2) polyoxyethylene glycol of mean molecular weight 6000.                .sup.(3) a foodstuffs quality surfactant: polyoxyethylene stearate.      

The active compound and glycine are granulated with an aqueous solutionof the PEG 6000, Myrj 52 and gelatin, prior to adding the magnesiumstearate and tableting in the usual way.

EXAMPLE XXVI Capsule formulation

                         mg/capsule                                               Active ingredient.sup.(1)                                                                          100.0                                                    PEG 6000.sup.(2)     280.0                                                    Myrj 52.sup.(3)      20.0                                                                          400.0                                                     .sup.(1) mean particle diameter less than 3 microns.                          .sup.(2) and .sup.(3) as in Example XXV                                  

The active compound is ball-milled in water to achieve the smallparticle size, mixed with the PEG 6000 and Myrj 52 as a paste and thendried at 40°C. to form a powder which is then filled into capsules inthe usual way.

EXAMPLE XXVII Parenteral formulation

                   mg/ml                                                          Active ingredient                                                                            7.5                                                            sodium chloride                                                                              7.9                                                            sodium hydroxide                                                                             (sufficient in pH adjustment)                                  water          (sufficient to make up volume)                             

The active ingredient and sodium chloride are dissolved in sterile,pyrogen-free and carbon dioxide-free water under nitrogen, the pH isadjusted to 11.75 with 10% aqueous sodium hydroxide and the volume madeup with similar water. The solution is then filled into 5 or 10 ml.ampoules through a filter and autoclaved at 115°C. for 30 minutes.

What is claimed is:
 1. A compound selected from the group consisting of##SPC10##and the salts thereof with pharmaceutically acceptable cationswherein R¹ is 3-trifluoromethyl, chloro, bromo or fluoro; n and m areeach 2 or 3; R² and R³, when taken separately, are each alkyl having 1to 4 carbon atoms and R² and R³, when taken together, are alkylenehaving 2 to 4 carbon atoms.
 2. The compound of claim 1 wherein each ofR² and R³ is alkyl having 1 to 4 carbon atoms.
 3. The compound of claim2 wherein R¹ is chloro.
 4. The compound of claim 1 wherein R¹ is2-chloro, m and n are each 2, R² is 2-methyl and R³ is 6-methyl.